Desmetramadol (INNTooltip International Nonproprietary Name), also known as O-desmethyltramadol (O-DSMT), is an opioidanalgesic and the main active metabolite of tramadol.[2] Tramadol is demethylated by the liver enzyme CYP2D6[3] to desmetramadol in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with CYP2D6inactivating mutations.
Desmetramadol is commonly encountered as a designer drug online[4] in powder form or as an ingredient in pressed pills due to being unscheduled in many jurisdictions. Outside of its role as a metabolite, a chemical used in research, and as a recreational drug, desmetramadol has a very limited history of human usage and is not approved for medicinal use in any country as of 2025.
Pharmacology
Pharmacodynamics
(+)-Desmetramadol is a G-protein biased μ-opioid receptor full agonist.[5] It shows comparatively far lower affinity for the δ- and κ-opioid receptors.[6] The two enantiomers of desmetramadol show quite distinct pharmacological profiles;[7] both (+) and (−)-desmetramadol are inactive as serotonin reuptake inhibitors,[8] but (−)-desmetramadol retains activity as a norepinephrine reuptake inhibitor,[9] and so the mix of both the parent compound and metabolites contributes significantly to the complex pharmacological profile of tramadol. While the multiple receptor targets can be beneficial in the treatment of pain (especially complex pain syndromes such as neuropathic pain), it increases the potential for drug interactions compared to other opioids, and may also contribute to side effects. Desmetramadol is also an antagonist of the serotonin5-HT2C receptor, at pharmacologically relevant concentrations, via competitive inhibition.[10] This suggests that the apparent anti-depressant properties of tramadol may be at least partially mediated by desmetramadol, thus prolonging the duration of therapeutic benefit. Inhibition of the 5-HT2C receptor is a suggested factor in the mechanism of anti-depressant effects of agomelatine and maprotiline. The potential selectivity and favorable side effect profile of desmetramadol compared to tramadol, makes it more suitable for use as antidepressant, although clinical development appears to have stopped. Upon inhibition of the receptor, downstream signaling causes dopamine and norepinephrine release, and the receptor is thought to significantly regulate mood, anxiety, feeding, and reproductive behavior. 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others.[11]. Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex.[12] There is some mixed evidence that agomelatine, a 5-HT2Cantagonist, is an effective antidepressant.[13] Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex.
Pharmacokinetics
Metabolites
Desmetramadol is metabolized in the liver into the active metabolite N,O-didesmethyltramadol via CYP3A4 and CYP2B6. The inactive tramadol metabolite N-desmethyltramadol is metabolized into the active metabolite N,O-didesmethyltramadol by CYP2D6.[14]
Society and culture
Recreational use
An herbal remedy called Krypton was found to contain kratom leaf powder and desmetramadol. Krypton was reportedly linked to at least 9 accidental opioid overdose deaths in Sweden during 2010–2011.[15][16][17]
Medicinal use
Unusually for a compound that first came to prominence as a recreational designer drug, desmetramadol has recently been reevaluated as a potential novel analgesic drug for use in medicine, with its well studied pharmacology and toxicology as an active metabolite of the widely used analgesic drug tramadol offering advantages over more structurally novel alternatives. Human clinical trials have shown it to offer similar analgesic benefits to drugs such as oxycodone and fentanyl but with reduced respiratory depression and a comparatively favorable safety profile.[18][5]
Legality
United States
Desmetramadol is not a scheduled substance in the United States.
United Kingdom
Desmetramadol was made a Class A drug in the United Kingdom on 26 Feb 2013.[19]
↑ Borlak J, Hermann R, Erb K, Thum T (November 2003). "A rapid and simple CYP2D6 genotyping assay--case study with the analgetic tramadol". Metabolism. 52 (11): 1439–43. doi:10.1016/s0026-0495(03)00256-7. PMID14624403.
↑ Garrido MJ, Valle M, Campanero MA, Calvo R, Trocóniz IF (October 2000). "Modeling of the in vivo antinociceptive interaction between an opioid agonist, (+)-O-desmethyltramadol, and a monoamine reuptake inhibitor, (-)-O-desmethyltramadol, in rats". The Journal of Pharmacology and Experimental Therapeutics. 295 (1): 352–9. doi:10.1016/S0022-3565(24)38909-8. hdl:10171/21763. PMID10992001.
↑ Arndt T, Claussen U, Güssregen B, Schröfel S, Stürzer B, Werle A, Wolf G (May 2011). "Kratom alkaloids and O-desmethyltramadol in urine of a "Krypton" herbal mixture consumer". Forensic Science International. 208 (1–3): 47–52. doi:10.1016/j.forsciint.2010.10.025. PMID21112167.
↑ Bäckstrom BG, Classon G, Löwenhielm P, Thelander G (2010). "[Krypton--new, deadly Internet drug. Since October 2009 have nine young persons died in Sweden]". Läkartidningen. 107 (50): 3196–7. PMID21294331.
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